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For the past 2 decades, pharmacologic medical management to prevent first and recurrent ischemic stroke due to large and small artery atherothrombosis has focused on a 3-agent class approach: antithrombotic therapies, blood pressure– lowering medications, and low-density lipoprotein (LDL) cholesterol lowering with statins.1 However, in recent years randomized trials have demonstrated that several additional medical-pharmacologic strategies can confer additional protection. Because these advances have occurred incrementally and often with ischemic stroke prevention as just 1 component of general cardiovascular event prevention, they are not yet widely appreciated or used by general neurologists and vascular neurology clinicians. Increased awareness of these new agent classes and the evidence supporting them could help facilitate their routine addition to neurologic practice to attain the maximal possible reduction in stroke risk for patients.
LDL Cholesterol Lowering With Additional Agent Classes
Cholesterol absorption inhibitors (eg, ezetimibe) and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (alirocumab and evolocumab) have been widely demonstrated to significantly reduce LDL cholesterol levels, and their efficacy in reducing stroke has been demonstrated in clinical trials. A meta-analysis of 6 randomized clinical trials (n = 21 205 patients) indicated that ezetimibe added to statins compared with same-dose statins was associated with lower risk of nonfatal stroke (absolute risk, 2.7% vs 3.2%; risk ratio, 0.83; 95% CI, 0.71-0.97; number needed to treat = 184).2 A meta-analysis of 39 randomized clinical trials (n = 60 328 patients) showed that PCSK-9 inhibitors (alirocumab or evolocumab) added to maximally tolerated statins were associated with reduced ischemic stroke (absolute risk, 1.1% vs 1.5%; risk ratio, 0.78; 95% CI, 0.67-0.89; number needed to treat = 305).3
Evidence from these clinical trials has ushered in what many lipidologists have termed a “poststatin era,” in which statins are no longer the only well-tolerated cholesterol-lowering class of medications with proven benefit for stroke prevention. Additional effective agent classes are now available and can serve as the primary lipid-lowering therapy in statin-intolerant patients and, when needed, as effect-enhancing agents in statin-tolerant patients. Given the higher drug costs with the addition of these agents, they are most cost-effective when used for patients at higher risk of atherothrombotic ischemic stroke, such as in the secondary prevention rather than primary prevention setting.4
Eicosapentaenoic Acid Class Agents
Agents that increase levels of eicosapentaenoic acid, 1 of the 3 main omega-3 fatty acids, substantially lower serum triglyceride levels in a manner free of the adverse effects associated with niacin, and also have beneficial effects on cell membrane stabilization and lipid oxidation. In a randomized clinical trial that enrolled 8179 patients with established cardiovascular disease or with diabetes and other vascular risk factors, among patients with elevated triglyceride levels despite the use of statins, the risk of stroke was significantly lower among patients who received 4 g of icosapent ethyl daily than among those who received placebo (absolute risk, 2.4% vs 3.3%; hazard ratio, 0.72; 95% CI, 0.55-0.93; number needed to treat = 108).5 Although the risks of major bleeding and hemorrhagic stroke did not differ significantly between icosapent ethyl and placebo, cardiac arrhythmia requiring hospitalization was more common in the icosapent ethyl group (4.6 % vs 3.8%, respectively).
In a subanalysis of another trial, 1.8 g of highly purified eicosapentaenoic acid daily (n = 485) compared with no use of eicosapentaenoic acid (n = 457) reduced the risk of recurrent stroke among Japanese patients with a history of stroke and high cholesterol who were all receiving low-dose statin therapy (absolute risk, 6.8% vs 10.5%; hazard ratio, 0.80; 95% CI, 0.80-1.00; number needed to treat = 74).6 Conversely, in a randomized trial (n = 13 078 patients at high cardiovascular risk) of eicosapentaenoic acid combined with other omega-3 fatty acids, including docosahexaenoic acid, there was no effect on stroke reduction.7 Docosahexaenoic acid increases LDL cholesterol concentrations, which may offset the potential benefits of the stroke-protective effect that eicosapentaenoic acid provides.
Pioglitazone is a thiazolidinedione that increases insulin sensitivity in target tissues. A meta-analysis of 3 randomized clinical trials (n = 4980 patients) showed that pioglitazone compared with placebo was associated with reduced recurrent stroke risk in patients with ischemic stroke and insulin resistance, prediabetes, and diabetes mellitus (absolute risk, 6.4% vs 8.5%; hazard ratio, 0.68; 95% CI, 0.50-0.92; number needed to treat = 37).8 In patients without prior stroke, no significant association of pioglitazone with incident stroke was observed. Randomized clinical trials also showed that the potential risk of heart failure and weight gain can be mitigated, even eliminated, by excluding patients with a history of heart failure, using safety algorithms that trigger dose reduction of pioglitazone, and adding sodium-glucose cotransporter 2 inhibitors or dulaglutide to pioglitazone.
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increase the synthesis of insulin by stimulating pancreatic islet cells and reducing glucagon secretion. A meta-analysis of 7 randomized clinical trials (n = 56 004) of patients with type 2 diabetes at high cardiovascular risk found that GLP-1 RAs were associated with a reduced rate of stroke (absolute risk, 2.6% vs 3.0%; hazard ratio, 0.84; 95% CI, 0.76-0.93; number needed to treat = 250).9 Homogeneous benefit was observed on stroke reduction with 6 of the 7 evaluated agents: albiglutide, exenatide, liraglutide, dulaglutide, subcutaneous semaglutide, and oral semaglutide. In contrast, lixisenatide did not show an effect, potentially related to shorter follow-up, higher use of concomitant statin therapy, and lower adherence to study medication in the pivotal trial. These data indicate that the preponderance of GLP-1 RAs could help reduce stroke risk in patients with type 2 diabetes who are at elevated cardiovascular risk.
A meta-analysis of 13 randomized clinical trials (n = 65 812 patients) conducted in countries without mandatory folic acid food fortification showed that folic acid supplementation was associated with reduced stroke (absolute risk, 3.1% vs 3.7%; risk ratio, 0.85; 95% CI, 0.77-0.95; number needed to treat = 182).10 The benefit was observed mostly in patients receiving folic acid alone or a combination of folic acid and minimal cyanocobalamin (absolute risk, 2.5% vs 3.3%; risk ratio, 0.75; 95% CI, 0.66-0.86; number needed to treat = 120).10 However, folic acid had no benefit for coronary artery disease prevention and had no benefit on stroke prevention for people living in countries with folic acid mandatory fortification.
In summary, although antithrombotic agents, blood pressure–lowering drugs, and LDL cholesterol lowering with statins form the cornerstone of stroke prevention, emerging evidence from randomized trials indicates that, when added to this regimen, select agents in 6 additional pharmacologic classes could further reduce large and small artery atherosclerotic stroke in appropriate patients (Table). Even as additional trials are performed, sufficient randomized trial data have already accumulated to support the judicious use by clinicians of these expanded therapeutic options to tailor a comprehensive multimodal strategy for optimal stroke prevention.
Corresponding Author: Jeffrey L. Saver, MD, UCLA Stroke Center and Department of Neurology, University of California, Los Angeles, 300 Medical Plaza Driveway B200, Los Angeles, CA 90095 (firstname.lastname@example.org).
Published Online: July 1, 2021. doi:10.1001/jama.2021.9917
Conflict of Interest Disclosures: Dr Saver reported serving as a scientific consultant advising on stringent clinical trial design to Amgen and Boehringer Ingelheim and serving on a clinical trial data and safety monitoring board for Novo Nordisk. No other disclosures were reported.
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Lee M, Ovbiagele B, Saver JL. Intensive Medical Management to Prevent Large and Small Artery Atherothrombotic Stroke: Time to Expand the Horizon. JAMA. 2021;326(3):217–218. doi:10.1001/jama.2021.9917
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